Anaplastic large cell lymphoma (ALCL) constitutes about 8 percent of non-Hodgkin's lymphomas in the general population and 25 percent in patients with human immunodeficiency virus (HIV) infection. All ALCL express the tumor necrosis factor (TNF) receptor family member CD30. More than 60 percent of the cases of ALCL in the non-HIV population are caused by activation of the protein tyrosine kinase anaplastic lymphoma kinase (ALK). ALK is usually activated by a 2:5 chromosomal translocation that produces a fusion with nucleophosmin (NPM), called NPM-ALK. Very little is known about the signal transduction pathways activated by NPM-ALK and thus, how it causes lymphoma. ALCL is unique because CD30 stimulation arrests cell growth. Although antibodies to CD30 are being used as therapy, the mechanism by which they arrest cell growth is not known. Our goals are to develop a foundation of knowledge about the signaling pathways necessary for NPM-ALK to cause lymphoma and to delineate the pathway by with CD30 stimulation arrests growth in ALCL. Phosphoinositide 3-kinase (PI3K), signal transducer and activator of transcription (STAT) 5 and phospholipase C gamma, are activated by NPM-ALK. Our studies suggest NPM-ALK phosphorylates the scaffolding proteins Gab2 and IRS-1 and thereby activates PI 3-kinase and probably STAT 3 and 5. We will determine the pathways by which NPM-ALK activates PI3K and STAT proteins and the importance of these pathways for lymphomagenesis. We will use both biochemical and genetic approaches to answer these questions. Our studies indicate that CD30 causes growth arrest as a result of inhibition of PI3K and induction of the cyclin- dependent kinase inhibitor, p21waf1. Using primarily a biochemical approach, we will establish the signaling pathway by which CD30 activation arrests cell growth in ALCL. The results of these studies should provide critical insights into how ALCL develops and how CD30 stimulation works as therapy. This knowledge may also help in developing treatment for other CD30 positive lymphomas and understanding how other oncogenes cause cancer.